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Letter

Nature 437, 281-285 (8 September 2005) | doi:10.1038/nature03914; Received 10 March 2005; Accepted 14 June 2005; Published online 10 July 2005

Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development

Abdolrahman S. Nateri1, Bradley Spencer-Dene2,3 & Axel Behrens1

  1. Mammalian Genetics Laboratory,
  2. Experimental Pathology Laboratory, CR UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
  3. Department of Histopathology, Imperial College London, UK

Correspondence to: Axel Behrens1 Correspondence and requests for materials should be addressed to A.B. (Email: axel.behrens@cancer.org.uk).

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The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, the activity of which is augmented in many tumour types1. An important mechanism in the stimulation of AP-1 function is amino-terminal phosphorylation of c-Jun by the c-Jun N-terminal kinases (JNKs)2. Phosphorylated c-Jun is biologically more active, partially because it acquires the ability to interact with binding partners. Here we show that phosphorylated c-Jun interacts with the HMG-box transcription factor TCF4 to form a ternary complex containing c-Jun, TCF4 and beta-catenin. Chromatin immunoprecipitation assays revealed JNK-dependent c-Jun–TCF4 interaction on the c-jun promoter, and c-Jun and TCF4 cooperatively activated the c-jun promoter in reporter assays in a beta-catenin-dependent manner. In the ApcMin mouse model of intestinal cancer6, genetic abrogation of c-Jun N-terminal phosphorylation3 or gut-specific conditional c-jun inactivation4, 5 reduced tumour number and size and prolonged lifespan. Therefore, the phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/beta-catenin, two distinct pathways activated by WNT signalling.

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